Cellular senescence is a stable form of proliferative arrest that acts as a potent barrier to cancer development and may contribute to various age-related diseases. This project originated from our observation that oncogenic Ras proteins can trigger senescence of primary cells through Rb and p53 dependent mechanisms as part of a then novel tumor suppressive mechanism. Subsequently we studied the underlying mechanisms by which Rb, p53, and chromatin modifying activities act to promote arrest, and showed how non-cell autonomous aspects of the senescence program trigger a form of immune surveillance involving NF-kB that modulates the tissue microenvironment and can promote senescent cell clearance. We also showed how signals that trigger senescence act to limit the aberrant self-renewal of stem and progenitor cells, and how the senescence program acts more broadly to limit certain wound healing responses and contribute to the cytotoxic action of certain drugs. Most recently, we showed that senescence of stromal cells during liver damage could reduce the occurrence of epithelial tumors in a non-cell autonomous manner. We propose to continue to explore the roles and regulation of cellular senescence, with an increased emphasis on how senescent cells influence the tissue microenvironment - a process involving the senescence-associated secretory phenotype (SASP). Thus, we will continue to identify factors that control regulation of SASP, and study how these influence senescence cell surveillance in different pathological contexts. We will explore how SASP factors impact tissue damage responses, primarily in the liver, and how they influence tumorigenesis in the context of pancreatic carcinoma, a pathophysiological context in which senescence plays a protective role. Finally, we will establish how restoring senescence to tumor cells impact tumor progression, assessing the magnitude and mechanisms of anti-tumor responses. Our approach interrogates the senescence program at many levels using hypothesis driven and non-biased approaches, and incorporates new RNAi technology and unique animal models to dissect the process in vivo. These tools, developed exclusively in our laboratory, enable a seamless integration of mechanistic and biological studies, in vitro and in vivo, and allow us to efficiently explore a range of biological questions in a time and cost effective manner. We expect our studies to further assemble an important tumor suppressor network that limits cancer development and may contribute to range of age related diseases; they will also define targets and strategies for modulating cellular senescence for therapeutic purposes.